Kinetic Advantage of Intrinsically Disordered Proteins in Coupled Folding–Binding Process: A Critical Assessment of the “Fly-Casting” Mechanism

Huang, Yongqi; Liu, Zhongfan

doi:10.1016/j.jmb.2009.09.010

Cited by 250 publications

(313 citation statements)

References 137 publications

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“…41 However, this size of the binding region is not uncommon among disordered proteins. 15,24 In this context, we note that regions outside of the binding surface of intrinsically disordered proteins might influence their association kinetics, either through attractive or repulsive electrostatic forces. We have not addressed this issue here, but the association rate constant for the C-terminal domain of the E6 protein (72 residues) is almost identical to that of its C-terminus used in the present study.…”

Section: Resultsmentioning

confidence: 99%

“…According to the socalled "fly-casting" scenario, disordered proteins may quickly form a high energy complex with the physiological partner, which would be locked in place by the subsequent folding reaction. 14 A potential advantage of the intrinsic disorder would then lie in the increased probability to capture a target ligand, 15 even with only moderate affinity. It is of critical importance to address these issues from a biophysical perspective and clarify the role of disorder in protein-ligand recognition.…”

Section: Introductionmentioning

confidence: 99%

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Side-Chain Interactions Form Late and Cooperatively in the Binding Reaction between Disordered Peptides and PDZ Domains

et al. 2011

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Intrinsically disordered proteins are very common and mediate numerous protein-protein and protein-DNA interactions. While it is clear that these interactions are instrumental for the life of the mammalian cell, there is a paucity of data regarding their molecular binding mechanisms. We have here used short peptides as a model system for intrinsically disordered proteins. Linear free-energy relationships based on rate and equilibrium constants for the binding of these peptides to ordered target proteins, PDZ domains, demonstrate that native side-chain interactions form mainly after the ratelimiting barrier for binding, in a cooperative fashion. This finding suggests that these disordered peptides first form a weak encounter complex with non-native interactions.The data do not support the recent notion that the affinities of intrinsically disordered proteins towards their targets are generally governed by their association rate constants.Instead, we observe the opposite for peptide-PDZ interactions, namely that changes in K d correlate with changes in k off .3

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Side-Chain Interactions Form Late and Cooperatively in the Binding Reaction between Disordered Peptides and PDZ Domains

et al. 2011

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“…In the fly-casting scenario, a protein may bind from a relatively large distance, thereby enhancing its capture radius: The tradeoff is between the entropy cost from extending a subdomain and the energy gained upon binding to a target. Although the disordered proteins may have slower translational diffusion comparing to globular proteins, their intrinsic flexibility imposes fewer constraints on binding and therefore they may have faster binding to their binding partners (10,15). It is possible that the biological function of downhill and ultrafast folding (16)(17)(18)(19)(20) is to achieve fast binding via fly casting.…”

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confidence: 99%

Capillarity theory for the fly-casting mechanism

Trizac

Levy

Wolynes

2010

Proc. Natl. Acad. Sci. U.S.A.

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Biomolecular folding and function are often coupled. During molecular recognition events, one of the binding partners may transiently or partially unfold, allowing more rapid access to a binding site. We describe a simple model for this fly-casting mechanism based on the capillarity approximation and polymer chain statistics. The model shows that fly casting is most effective when the protein unfolding barrier is small and the part of the chain which extends toward the target is relatively rigid. These features are often seen in known examples of fly casting in protein-DNA binding. Simulations of protein-DNA binding based on wellfunneled native-topology models with electrostatic forces confirm the trends of the analytical theory.binding mechanism | disordered proteins | fast folding | protein folding I t is becoming clear that protein folding and protein functioning are often overlapping processes. For cooperatively folding proteins, a free energy barrier separates the folded configurations from the unfolded ones. If this barrier is sufficiently high, we expect the traditional "function follows folding" paradigm to be valid. Many proteins however are unfolded before they function (1-5). Other proteins have native ensembles separated by only a small barrier from their disordered states. It has recently been argued that in some circumstances there may be no folding barrier at all (6-8). Clearly in all these cases folding and function must be coupled. In addition, partially surmounting the folding barrier, even if it is high, may short circuit the otherwise large barriers that would accompany allosteric changes, if the protein were required to always remain intact. These two ways of coupling the folding landscape and the functional landscape have been termed "fly casting" (9-11) (for the binding process) and "cracking" (for allosteric change) (12)(13)(14). In the fly-casting scenario, a protein may bind from a relatively large distance, thereby enhancing its capture radius: The tradeoff is between the entropy cost from extending a subdomain and the energy gained upon binding to a target. Although the disordered proteins may have slower translational diffusion comparing to globular proteins, their intrinsic flexibility imposes fewer constraints on binding and therefore they may have faster binding to their binding partners (10,15). It is possible that the biological function of downhill and ultrafast folding (16)(17)(18)(19)(20) is to achieve fast binding via fly casting. In this paper, we explore the interplay between the fly casting and the folding barrier using the capillarity model for protein folding, which in its simplest form ignores many of the structural features of the native protein.Despite the intrinsic complexity of the folding of a random heteropolymer, most proteins have evolved to fold via a funneled energy landscape (21,22). This evolved feature greatly simplifies the physics of the folding process because the primary free energy scales involved are then the entropy of organizing the chain into a sp...

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“…5 In addition, it was also demonstrated that the speed of a protein's ability to bind to its partner(s) increased drastically in proteins with intrinsically disordered regions when compared to their structured, globular counterparts. 6 Intrinsically disordered regions known as linker regions can hold two globular portions of a protein in close proximity with each other, while still allowing a large amount of flexibility in their spatial relationship with one another. 7 This perhaps allows a protein with IDRs to bind with several binding partners simultaneously under changing cellular states.…”

Section: Introductionmentioning

confidence: 99%

Intrinsically Disordered Proteins: Controlled Chaos or Random Walk

Howton

Zhan

Sun

et al. 2016

IJPB

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Traditional conventions that a protein's sequence dictates its definitive, tertiary structure, and that this fixed structure provides the protein with the ability to carry out its designated role(s) are still correct but not for all proteins. Research over the past decade discovered that several key proteins possess intrinsically disordered regions (IDRs) that are crucial to their ability to perform specific functions and are observed clustered together within important classes of proteins. In this review, we aim to demonstrate how free energy landscapes, molecular dynamics simulations, and homology modeling are helpful in understanding key conformational dynamics of intrinsically disordered proteins (IDPs). Additionally, we use a list of predicted IDPs found in Arabidopsis to identify chromatin organizers and transcriptional regulators as being highly enriched in IDPs. Furthermore, we focus our attention to specific proteins within these families such as HAC5, EFS, ANAC019, ANAC013, and ANAC046. Future studies are needed to experimentally identify additional IDPs and their binding mechanisms.

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Kinetic Advantage of Intrinsically Disordered Proteins in Coupled Folding–Binding Process: A Critical Assessment of the “Fly-Casting” Mechanism

Cited by 250 publications

References 137 publications

Side-Chain Interactions Form Late and Cooperatively in the Binding Reaction between Disordered Peptides and PDZ Domains

Side-Chain Interactions Form Late and Cooperatively in the Binding Reaction between Disordered Peptides and PDZ Domains

Capillarity theory for the fly-casting mechanism

Intrinsically Disordered Proteins: Controlled Chaos or Random Walk

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